In males, prostate cancer is now the most common (more than 100,000 cases will be diagnosed in 1991) and the second leading cause of cancer death. The disease is characterized by latent and overt forms, the latter of which is detectable in 40-50% of autopsied men over 40. The disease is progressive and clinical forms increase with age. The heparin-binding fibroblast growth factor (FGF) family of polypeptides and its receptor (FGF-R) has been firmly implicated in support of prostate epithelial and stromal cell growth and possibly differentiation. The FGF and FGF-R family is extremely heterogenous at the molecular level. The factor family consists of homologous products of seven genes while the receptor family consists of splice variations of four genes which result in structural isoforms that have impact on most known functions of receptors (ligand- binding, dimerization, tyrosine kinase activity, autophosphorylation on tyrosine, exogenous phosphorylation on ser/thr, and metabolism). This makes the family an excellent candidate for molecular changes that lead to unregulated growth and differentiation during prostate tumor progression and an excellent target for regulation by other growth factors. This project will determine the expression pattern of the seven members of the FGF ligands and splice variants of the flg FGF-R1 and bek FGF-R2 receptor genes in the epithelial and stromal cells of model rat prostate tumors as they progress from the relatively benign differentiated state to the highly lethal malignant metastatic states. This will be accomplished by combinations of cell culture, transplantable tumor in vivo, molecular biology and protein chemistry technologies. It will test the hypothesis that the receptor family is modified by negative regulators of normal epithelial cell growth (TGF-B and other cytokines) and cholera toxin which is an artificial stimulant of normal epithelial cell growth that is by- passed by tumor cells. The key hypothesis to be tested is that normal epithelial cell growth and differentiation is controlled by directional stromal to epithelial cell paracrine signals that are subverted by activation of autocrine loops within the epithelial cells. Change from ordered paracrine control to abnormal autocrine control lies within changes in expression of isoforms of both FGF ligand and receptor genes, the latter of which is predominantly changes in specific splice variants.